EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms
EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms
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DOI：
10.1158/0008-5472.can-05-3090
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Maity, A
中科院分区：
文献类型：
--
作者：
Pore, N;Jiang, ZB;Maity, A
表皮生长因子受体（EGFR）抑制剂可以降低血管内皮生长因子（VEGF）表达和肿瘤血管生成。在当前的研究中，我们使用两种已在临床使用的药物吉非替尼（易瑞沙）和厄洛替尼（特罗凯）研究了发生这种情况的分子途径。吉瑞替尼在 SQ20B 鳞状细胞癌细胞中减少 VEGF 表达，而这些细胞中 Akt 的腺病毒表达则相反。常氧条件下吉非替尼下调启动子活性不需要位于 VEGF 启动子中约 -1 kbp 的缺氧诱导因子 1 (HIF-1) 结合位点。此外，该药物还降低了含有-88/+54 区域的报告基因的活性。在凝胶位移测定中，吉非替尼导致与 VEGF 启动子的 -88/-66 区域相对应的标记 DNA 寡核苷酸探针的延迟减少，该区域包含 Sp1 结合位点。吉非替尼对 VEGF 启动子活性和 DNA 结合的这些影响均被 Akt 表达逆转。吉非替尼存在时 Sp1 的磷酸化降低。吉非替尼还通过降低 HIF-1 α 表达来降低 VEGF 表达。这是由于蛋白质翻译减少而 HIF-1 α mRNA 水平没有任何变化所致。总之，这些结果表明吉非替尼通过减少 Sp1 与近端核心 VEGF 启动子的结合和下调 HIF-1 α 表达来降低 VEGF 表达。厄洛替尼在 SQ20B 中和吉非替尼在 HSC3 鳞状癌细胞中也获得了类似的结果。这些结果表明EGFR抑制剂降低VEGF表达至少有两种不同的机制。
Epidermal growth factor receptor (EGFR) inhibitors can decrease vascular endothelial growth factor (VEGF) expression and tumor angiogenesis. In the current study, we investigate the molecular pathways by which this occurs using two drugs that have been used in the clinic, gefitinib (Iressa) and erlotinib (Tarceva). The decrease in VEGF expression by geritinib in SQ20B squamous cell carcinoma cells was opposed by adenoviral expression of Akt in these cells. The hypoxia-inducible factor-1 (HIF-1) binding site located at approximately -1 kbp in the VEGF promoter was not required for down-regulation of promoter activity by gefitinib under normoxia. Furthermore, the drug decreased activity of a reporter containing the -88/+54 region. In a gel shift assay, gefitinib led to decreased retardation of a labeled DNA oligonucleotide probe corresponding to the -88/-66 region of the VEGF promoter, which contains Sp1 binding sites. These effects of gefitinib, on VEGF promoter activity and DNA binding were both reversed by Akt expression. Phosphorylation of Sp1 was decreased in the presence of gefitinib. Gefitinib also decreases VEGF expression by decreasing HIF-1 alpha expression. This occurs due to decreased protein translation without any change in the level of HIF-1 alpha mRNA. Together, these results suggest that gefitinib decreases VEGF expression both by decreasing Sp1 binding to the proximal core VEGF promoter and by down-regulating HIF-1 alpha expression. Similar results were obtained with erlotinib in SQ20B and gefitinib in HSC3 squamous carcinoma cells. These results indicate that there are at least two separate mechanisms by which EGFR inhibitors decrease VEGF expression.